Ischemic Area Infusion And Regional Hypothermia: A Potential Therapy In Stroke
Clinically, there are no effective therapeutic tools for amelioration of cerebral ischemia/reperfusion caused by stroke. It has been emphasized that ischemia/reperfusion injury is initiated by a series of events occurring at the blood-vascular-parenchymal interface, leading to inflammatory injury, disruption of endothelial integrity, and neuron death. B rain cooling is a remarkable neuroprotectant in stroke therapy if applied soon after onset of ischemia. Due to management difficulties, hypothermic induction by surface cooling in current clinical settings is vastly limited. Results from our recent studies indicate that highly localized intra-arterial “flushing” of the ischemic territory prior to reperfusion significantly reduces brain injury in experimental stroke. The mechanisms of neuroprotection conferred by hypothermia or vascular infusion are thought to be multifunctional. This leads to a new hypothesis that local intraarterial cold hypertonic solution infusion, concurrent with regional cerebral hypothermia in ischemic areas prior to reperfusion, synergistically minimizes brain injury. This may provide the ultimate neuroprotective “cocktail” that limits inflammation and neurovascular disruption during reperfusion. In our laboratory, we define the therapeutic and systematic optimization of a combined infusion and cooling procedure in our stroke model by evaluating long-term motor deficits, brain infarct volume, as well as cerebral and pulmonary edema. W e also elucidate protective mechanisms of the novel model that targets the brains vascular-parenchymal interface by reducing inflammatory mediators, endothelial activation of nuclear factor kappa-B, leukocyte infiltration, matrix metalloproteinase expression, and blood-brain barrier disruption.
Results from these studies will provide fundamental information on the establishment of a novel therapeutic procedure in stroke beyond the levels achieved by current therapy. Intravascular cold infusion into the ischemic region, which combines recanalization of the occluded middle cerebral artery (mechanically or thrombolytically) and administration of neuroprotective drugs, may improve outcome in stroke patients.
Recent Publications in Peer-reviewed Journals
Ding, Y., Yao , B., Yang, D-Z, Park, H., McAllister J.P., Diaz, FG. (2002) Pre-reperfusion Flushing of Ischemic Territory: A Therapeutic Study on Ischemia-reperfusion Injury in Stroked Rats Using Histological and Behavioral Assessments. Journal of Neurosurgery . 96:310-319.
Ding, Y., Li, J., Phillis J.W. Rafols J.A., Diaz, FG. (2002) Pre-reperfusion Flushing into Ischemic Territory Reduces Inflammatory Injury in Rat with Transient Middle Cerebral Artery Occlusion. Stroke . 33: (10) 2492-2498.
Ding Y., Young C, Li C, Luan X, McAllister JP, II, Clark J, Diaz FG (2003) Reduced Inflammatory Mediator expression by Pre-reperfusion Infusion into Ischemic Territory : A real-time Polymerase Chain Reaction Analysis.Neurosci.Lett. 353: 173-176.
Ding YH; Li J, Rafols, JA, Ding, Y. (2004) Reduced Brain Edema and Matrix Metalloproteinase (MMP) Expression By Pre-reperfusion Infusion into Ischemic Territory in Rat. Neuroscience Letters. 372: 35-39.
Ding, Y., Li, J., Luan XD., Lai Q., McAllister J.P., Phillis, J.W., Guthikonda, M., Diaz, FG (2004) Neuroprotection of Regional Brain Cooling and Local Saline Infusion into Ischemic Territory in Rats with Transient Middle Cerebral Artery Occlusion. Neurosurgery . 54 (4):956-965.
Luan XD, Li J, McAllister JP, II, Clark J, Diaz FG, Fessler RD. , Ding Y. (2004) Regional Brain Cooling Induced by Local Saline Infusion into Ischemic Territory Reduces Brain Inflammation in Stroke. Acta Neuropathologica. 107:227-234.
Li J, Luan X, Clark J, Rafols JA, McAllister JP, II, Diaz, FG. Ding Y. (2004) Regional Brain Cooling Induced by Local Saline Infusion into Ischemic Territory Produced A Long-term Neuroprotection in Ischemic Rats Using a Behavioral Assessment. Neurological Res 26:677-683.